Prostaglandin D2 (PGD2) is a prostanoid and belongs to a class of chemical mediators that is synthesized by cells in response to stimuli, such as local tissue damage or hormonal stimuli, or by cellular activation pathways. Cells synthesize PGD2 from arachindonic acid by cyclooxygenase and other specific synthases in the pathway.
Upon stimulation, mast cells release PGD2 in major amounts and this release plays a major role in the etiology of respiratory disease, such as asthma and congestion. PGD2 achieves this effect by binding with either of two G-protein coupled receptors; these are designated the D-prostainoid (DP) receptor and the CRTH2 receptor.
PGD2 is known to have a clear role in the allergic inflammatory response. PGD2 is found at high levels in the bronchoalveolar lavage of asthmatics. Inhalation of PGD2 enhances eosinophilic and lymphocytic airway inflammation in allergic animal models and, by using CRTH2 knockout mice, it was demonstrated that PGD2 achieves this role by binding to the CRTH2 receptor. Hence, CRTH2 receptor antagonists would be expected to reduce the allergic inflammatory response caused by PGD2 and these compounds would be useful in the treatment or prevention of allergic/immune disorders.
Current drugs of choice for the treatment of chronic inflammatory airway disease, such as asthma or COPD, are synthetic glucocorticoids; examples of these compounds currently indicated for treatment of these disorders include fluticasone and mometasone. The difficulty with this class of compounds is that it possesses a number of systemic side-effects; these include adrenal suppression, altered bone metabolism and growth suppression in children. These side effects limit the dose that can be administered on a daily basis to the patient. While a non-steroidal class of therapeutics that inhibit bronchoconstriction exists (CysLT1 antagonists), this class of compounds has limited efficacy in achieving the endpoints of reducing inflammatory and improving in lung function when compared to the glucocorticoids. Therefore, a therapeutic that combines the efficacy of inhaled glucocorticoids without the side effects would constitute an advancement in this field.
Ramatroban is a therapeutic that was approved for the treatment of allergic rhinitis in Japan; the compound has the following structure:
Ramatroban was originally developed as a thromboxane antagonist. However, it was subsequently discovered that ramatroban also antagonizes to the CRTH2 receptor.
The literature reports other chemical classes of compounds that will antagonize the CRTH2 receptor. US 2009/0012102 to Actimis Pharmaceuticals discloses imidazo[1,2-C]pyrimidinylacetic acid derivatives and indicates that these compounds have excellent activity in antagonizing CRTH2 receptor. Actelion Pharmaceuticals (WO 2006/070325) discloses certain 2,3,4,9-tetrahydro-1H-carbazole derivatives as possessing the ability to antagonize the CRTH2 receptor and indicates that these derivative are useful in the treatment of both chronic and acute allergic/immune disorders. Oxagen (WO 2007/107772) discloses that salts of compounds of the formula:
possess CRTH2 antagonistic activity and indicates that these compounds possess surprising properties over the compounds disclosed in WO 2005/044260.
Quinazolinone derivatives are known in the art, albeit for other indications. WO 1998/26664 to E. I. du Pont de Nemours discloses compounds of the formula:
where G may be, inter alia, a fused phenyl ring. This published application teaches that these compounds have fungicidal activity. There are two US patents that issued from this published international application: U.S. Pat. Nos. 6,066,638 and 6,245,770. U.S. Pat. No. 6,255,311 discloses a related series of compounds with the same utility.
U.S. Pat. No. 4,183,931 discloses 2-ketoalkyl-4(3H)-quinazolinones of the formula:
where R2 is an aliphatic, cycloaliphatic, hydrocarbon aromatic or heterocyclic group of 1 to 10 carbons. These compounds are said to possess sedative-hypnotic and/or anticonvulsant activity.
EP 1 398 032 to PheneX Pharmaceuticals discloses 4-oxo-quinazolines of the formula:
where R6 may be groups such as —S—R7 or —N(R8)(R9) and R7, R8 and R9 may be groups such as H or substituted alkyl.
WO 2005/049613 to Merck discloses bicyclic pyrimidin-4-(3H)-one derivative of the formula:
where may be an optionally substituted phenyl ring, X may be oxygen, sulfur or nitrogen and Y is a group of the formula —(CR2R3)n(CO)p(NR4)qW. These compounds are said to modulate the vanilloid-1-receptor and are disclosed to be useful in the treatment of pain. Another publication also by Merck that discloses vanilloid-1-receptor modulators is WO 2006/122200.
Talukdar at al., Indian J. Chem. Sect. B, pp 41-15 (1977) disclose the following quinazoline derivative:
